1. Field of the Invention
The present invention relates generally to the field of cancer treatment. More particularly, the invention relates to anti-neoplastic injectable pharmaceutical compositions with enhanced stability.
2. Description of the Related Art
Various methods of stabilizing injectable pharmaceutical compositions containing taxoid anti-neoplastic agents have been disclosed. One method, disclosed in U.S. Pat. No. 5,504,102 to Bristol-Myers Squibb Company, deals with the treatment of Cremophor EL (a commercially available polyoxyethylated castor oil supplied by BASF) to be used in an injectable paclitaxel (an anti-neoplastic compound) pharmaceutical composition. The patent discloses the treatment of Cremophor EL with alumina or sufficient acid to reduce the level of carboxylate anions. According to the patent, carboxylate anions originate from the production of Cremophor EL and catalyze the degradation of paclitaxel. Although the mineral acid treatment and further processing of Cremophor EL yield substantially better stability than if the injectable were manufactured without an acid stabilizing agent for short-term storage conditions (i.e., 50.degree. C. for approximately 2 months), long-term stability studies (i.e., 40.degree. C./75% relative humidity for 6 months) indicate that paclitaxel is still susceptible to degradation. In addition, the mineral acid treatment strategy must be tightly controlled in order that the pH of the formulation, during manufacturing as well as in the finished dosage form, does not reach a level in which paclitaxel will decompose due to acid catalyzed hydrolysis mechanisms.
A second method for preventing paclitaxel degradation is disclosed in U.S. Pat. No. 5,733,888 to NaPro BioTheraputics Inc. According to this method, paclitaxel degradation is controlled by maintaining the pH of the finished formulation at or below a value of seven (7). The pH of the formulation can be adjusted by treating the Cremophor EL with an acid. The patent discloses that acids in powder form are preferred over those which contain water. Water is most likely avoided since in the presence of acids, water provides a vehicle as well as a reagent for acid catalyzed hydrolysis of paclitaxel, even at moderately acidic pH levels. Again, this type of treatment technology of the Cremophor EL must be tightly controlled in order to guard against pH deviations which could lead to hydrolytic degradation of the taxoid compound.
Other pharmaceutical formulations of taxoid compounds exist in which long-term shelf life is problematic. Several U.S. patents have been assigned to Rhone-Poulenc Rorer (U.S. Pat. No. 5,403,858, U.S. Pat. No. 5,438,072, U.S. Pat. No. 5,670,536, U.S. Pat. No. 5,698,582, U.S. Pat. No. 5,714,512) which address a formulation composed of a taxane compound dissolved in a surfactant selected from a group consisting of polysorbate, polyoxyethylene glycol, or hydrogenated castor oil, and essentially free of ethanol. Although reduction of ethanol has a therapeutic advantage, stability of these formulations is suspect. This is demonstrated by the directed storage of these products under refrigerated conditions.
Reduced long-term shelf life leads to increased manufacturing costs due to extensive consumption of raw materials and yields a product of inferior quality, both translating into higher costs to the patient. Therefore, a stabilization strategy is needed to prevent the degradation of taxoid anti-neoplastic compounds in injectable pharmaceutical compositions independent of the injectable solvent system.